Saliva as a non-invasive biomarker for chronic kidney disease: Challenges and potential in disease monitoring

Table 1 Comparison of saliva collection methods based on biomarker reliability, feasibility, and limitations

Collection method	Biomarker reliability	Feasibility	Major limitations
Spitting	High	Easy and patient-friendly	Inconsistent flow, variable technique
Passive drool	Moderate to high	Non-invasive, simple	Slow collection, risk of evaporation
Stimulated (paraffin chewing)	Moderate (flow-dependent dilution)	Simple, cost-effective	Contamination risk, requires compliance, time-sensitive processing
Stimulated (parotid)	Variable, biomarker-specific	Targeted gland sampling	Invasive, discomfort, specialized equipment needed
Oral rinse	Low (due to dilution)	Very easy and rapid	Dilution effect, unreliable concentrations
Salivette®	Moderate	Standardized device available	Absorption variability, potential contamination

Table 2 Summary of studies on salivary creatinine and urea for chronic kidney disease diagnosis

Ref.	Biomarker(s)	Sample size (CKD/control)	CKD stage(s)	Collection method	Statistical analysis	Correlation (r)	AUC	Assay type	Key findings	Limitations
Venkatapathy et al[61], 2014	Creatinine	105/37	Stage 4-5	Spitting	T-test, pearson, linear regression, ROC	0.73	0.96 (97.1% sensitivity and 86.5% specificity)	Enzymatic	High diagnostic accuracy in advanced CKD	No early-stage CKD data
Lasisi et al[57], 2016	Creatinine, urea	49/50	Mostly stage 4–5	Spitting	Mann-Whitney U, Spearman, ROC	Creatinine = 0.69, urea = 0.51	Creatinine: 0.97 (94% sensitivity and 85% specificity, urea: 0.89 (86% sensitivity and 93% specificity)	Enzymatic	Reflects serum levels, high diagnostic accuracy	Lacked early-stage representation
Pandya et al[62], 2016	Creatinine, urea	90/30	Not specified	Spitting	Kruskal-Wallis, Mann-Whitney U, Spearman	Creatinine = 0.97; urea = 0.97	NR	Enzymatic	Significant serum-saliva correlation	Variability in flow rate, method inconsistency
Pham[60], 2017	Creatinine, urea	112/108	All stages	Spitting	Spearman, linear regression, ROC	Creatinine = 0.90; urea = 0.73	Creatinine: 0.92 (86.5% sensitivity 87.2% and specificity), urea: 0.76 (82.9% sensitivity and 57.8% specificity	Spectrophotometric	Validated diagnostic utility in large sample	Cross-sectional, urban-based sampling bias
Bagalad et al[63], (2017)	Creatinine, urea	41/41	Not specified	Spitting	T-test, pearson, ROC	Creatinine = 0.65; urea = 0.81	Creatinine: 0.9 (93.0% sensitivity and 93.0% specificity), urea: 0.9 (93.0% sensitivity and 90.0% specificity)	Enzymatic	High diagnostic accuracy demonstrated	Inconsistencies in collection and assay protocols
Renda[56], 2017	Creatinine	35/28	Not specified (Pediatric)	Spitting	Kolmogorov-Smirnov, pearson, linear regression, ROC	r = 0.79	0.80 (82.9% sensitivity and 78.6% specificity)	Enzymatic	Strong serum-saliva correlation	Pediatric-only, small sample, no adult comparison
Nagarathinam et al[59], 2023	Urea	150/30	Stage 1–5	Spitting	T-test, ANOVA, pearson, ROC	0.51 ≈ 0.75	0.91 (88% sensitivity and 84% specificity)	Enzymatic	Strong stage-wise diagnostic potential	Periodontal status, diet, hydration not controlled
Liyanage et al[64], 2024	Creatinine, urea	100/0	Stage 2–5	Spitting	Pearson, paired t-test, χ2, ROC	Creatinine = 0.98; urea = 0.94	≥ 0.99 (sensitivity and specificity: NR)	Enzymatic	Correlations unaffected by age/sex	No healthy controls included for comparison

AUC: Area under the curve; CKD: Chronic kidney disease; NR: Not reported; PTH: Parathyroid hormone; ROC: Receiver operating characteristic.

Table 3 Summary of studies on salivary calcium and parathyroid hormone for chronic kidney disease diagnosis

Ref.	Biomarker(s)	Sample size (CKD/control)	CKD stage(s)	Collection method	Statistical analysis	Correlation (r)	AUC	Assay type	Key findings	Limitations
Rodrigues et al[65], 2016	Calcium, PTH	60/37	Stage 5	Stimulated (paraffin chewing)	T-test, pearson, simple linear regression	Calcium: -0.13, PTH: 0.03	NR	Colorimetric	No significant correlation between serum and saliva	Small sample size
Rajolani et al[66], 2024	Calcium, PTH	29/0	NR	Spitting method	Paired t-test, pearson's correlation	NR	NR	Enzymatic	No significant serum-saliva correlation for calcium and PTH	Healthy controls are needed for better comparison

AUC: Area under the curve; CKD: Chronic kidney disease; NR: Not reported; PTH: Parathyroid hormone; ROC: Receiver operating characteristic.